Cancer initiation and progression is determined by both genetic and epigenetic changes. Histone deacetylases (HDAC) are enzymes actively involved in chromatin remodeling and are aberrantly expressed and dysregulated in multiple types of human cancers. HDAC inhibitors (HDACi) represent an emerging class of drugs that exhibit a broad range of anticancer effects. As a result of their broad anticancer activity, HDACi are particularly well suited for synergistic combinations with conventional anticancer drugs. The ability to selectively deliver combinations of HDACi with conventional anticancer drugs has the potential to greatly enhance the treatment repertoire and efficacy for many types of cancers. The objective of this proposal is to develop nanoparticles capable of targeted, simultaneous, combined delivery of HDACi and anticancer drugs into lung cancer. The central hypothesis is that using novel biodegradable polycaprolactones with high content of pendant HDACi moieties (HDPCL) will enhance activity of multiple anticancer drugs delivered by nanoparticles prepared from HDPCL and targeted to lung tumors overexpressing mucin 1. The hypothesis is based on our current studies with HDPCL and the well-established role of HDAC inhibition in enhancing activity of multiple anticancer drugs. The overall objective of this application will be achieved b pursuing three specific aims: 1) synthesize biodegradable polycaprolactones with pendant HDACi groups (HDPCL); 2) evaluate if delivery by HDPCL improves drug activity in lung cancer cells; and 3) determine in vivo if HDPCL delivery improves antitumor activity in orthotopic lung cancer model. The approach is innovative because of the novel type of biodegradable polyesters with high HDACi loading (up to 59 wt %) and controlled HDACi release suitable for combination delivery of conventional anticancer drugs. The proposed research is significant because it will establish a widely applicable and versatile method for simultaneous, targeted delivery of chemotherapeutics and HDACi to improve delivery and therapeutic outcome in lung cancer. Approaches that rely on combinations of active agents with synergistic or additive effect have the potential to greatly enhance the efficacy of cancer therapy.